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Current Molecular Pharmacology

George P Chrousos, Emmanouil Zoumakis
The Corticotropin-releasing Hormone (CRH) mammalian family members include CRH, urocortin I, Stresscopin (SCP) and Stresscopin-related peptide (SRP), along with the CRH receptors type 1 (CRHR1) and type 2 (CRHR2), and CRH-binding protein (CRH-BP). These family members differ in their tissue distribution and pharmacology. Several studies have provided evidence supporting an important role of this family in the regulation of the neuroendocrine and behavioral responses to stress. Regulation of the relative contribution of CRH and its homologs and the two CRH receptors in brain CRH pathways may be essential in coordinating physiologic responses to stress...
January 9, 2017: Current Molecular Pharmacology
Noelia Perez-Diaz, Igor Pushkarskya, Nadia Oweisa, Lisa A Lionea, Louise S Mackenzie
BACKGROUND: The ubiquitous nuclear receptor PPARβ/δ is increasingly being studied in regards to numerous diseases including diabetes following on the finding that PPARβ/δ agonist GW0742 controls Type 1 Diabetes in rats. Studies have shown that GW0742 has off target, non- PPARβ/δ effects in the cell although there are some key questions that remain to be addressed in respect to the significance of this control on vascular tone. METHODS: Using isometric organ baths, rat aorta rings were exposed to ROCK inhibitors and the changes in contraction and dilation measured...
December 29, 2016: Current Molecular Pharmacology
Ramsés Jiménez-Moreno, Adrián Amaury Farret-Ramos, Adriana Valle-Ayala, Niurka Trujillo-Paredes, Eric Murillo-Rodríguez
BACKGROUND: Modafinil (MOD) is a waking-promoting compound that is used for treatment of sleep disorders such as sleepiness and narcolepsy. Despite its efficiency, there are missing pieces of evidence regarding the mechanism of action of MOD at molecular level. For example, current data have demonstrated that MOD induces alertness by activating several wake-related neurotransmitter receptors, including dopamine 1 (D1) receptor. Nevertheless, an intriguing point highlights that MOD might be activating intracellular elements bounded to D1 receptor, such as cAMP response element-binding (CREB) or mitogen-activated protein kinase (MAP-K) expression...
December 14, 2016: Current Molecular Pharmacology
Clémentine Puech, Morgane Chatard, Delphine Felder-Flesch, Nathalie Prevot, Nathalie Perek
The high degree of malignancy of tumour cells is linked to alterations of many physiological parameters like the intracellular pH (pHi). The pHi in cancer cell line is regulated by the anhydrase carbonique IX (CA IX). The main enzymatic function of the CA IX protein is to catalyze the hydration of carbon dioxide into bicarbonate ions and protons. Inhibiton of transmembrane tumor associated isozyme carbonic anhydrase IX (CA IX) with specific inhibitors is a promising and expanding field as CA IX is involved in tumor progression...
November 28, 2016: Current Molecular Pharmacology
Hesham Fahmy, Bahimanna Kuppast, Mohamed Teleb Ismail
Corticotropin-releasing factor (CRF) can be considered a very important hormone or a chemical mediator. It works closely with other systems to regulate the manner through which the body may respond to stress. Thus it affect many biological processes associated with stress. Dysfunction of this system has also been correlated with various diseases such as major depression, anxiety, drug addiction and eating disorders. Rationally, this means that interfering with binding of CRF to its intended receptors can be an attractive target for drug design aiming at developing new medications for many ailments that are associated with stress such as depression, anxiety and stress-induced relapse in drug addiction...
November 1, 2016: Current Molecular Pharmacology
Maria Venihaki, Olga Rassouli, George Liapakis
Hypothalamic corticotrophin-releasing hormone (CRH) has a key role in coordinating and controlling complex responses to stress, both systemically, by stimulating the expression of the pituitary POMC gene, and thus, resulting in increased production of ACTH and adrenal glucocorticoid release, and locally since CRH has been identified in several peripheral tissues. CRH seems to exert its effects through interaction with two known so far receptors, CRF1R and CRF2R. The mRNA and protein of CRH family of peptides and their receptors are expressed at several peripheral tissues including rodent and human skin...
October 26, 2016: Current Molecular Pharmacology
Hamidreza Famitafreshi, Morteza Karimian, Sulail Fatima
INTRODUCTION: Addiction to drugs of abuse is a devastating condition which results in deterioration of brain function. On the other hand, social isolation also produces cognitive deficits such as learning and memory impairment. This study was designed to evaluate the potential negative synergistic effects of social isolation and morphine addiction on brain functions. METHODS AND MATERIAL: One hundred and two Sprague-Dawley rats were randomly divided into four groups for assessing neurogenesis and behaviour: group-housed, isolated, morphine-treated group-housed and morphine-treated isolated groups...
August 22, 2016: Current Molecular Pharmacology
Marcos Brandão Contó, Marco Antonio Campana Venditti
Epilepsy is one of the most prevalent neurological disorders worldwide, but its underlying mechanisms have not yet been clarified. Among the possible molecular mechanisms that underlie its occurrence are those that are responsible for the neuronal ionic gradient, including the transmembrane enzyme Na+,K+-adenosine triphosphatase (ATPase). Na+,K+-ATPase plays an important role in controlling neuronal excitability, and it is believed to be related to the pathophysiology of epilepsy. However, the specific isozymes that may be related to this neurological disorder remain to be determined...
April 7, 2016: Current Molecular Pharmacology
Behzad Yeganeh, Amir A Zeki, Nicholas J Kenyon, Saeid Ghavami
No abstract text is available yet for this article.
January 14, 2016: Current Molecular Pharmacology
S Zahra Bathaie, Mahboobeh Ashrafi, Mahshid Azizian, Fuyuhiko Tamanoi
Mevalonate (MVA) is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) by HMG-CoA reductase (HMG-CoAR). MVA is further metabolized to farnesyl pyrophosphate (FPP), a precursor of cholesterol and sterols. FPP is also converted to geranylgeranyl pyrophosphate, and these lipids are used for post-translational modification of proteins that are involved in various aspects of tumor development and progression. Many studies showed that the MVA pathway is up-regulated in several cancers such as leukemia, lymphoma, multiple myeloma; as well as breast, hepatic, pancreatic, esophageal and prostate cancers...
January 12, 2016: Current Molecular Pharmacology
Eftekhar Eftekharpour, Nagakannan Pandian, Mohamed Ariff Iqbal, Qi Min Chen
The mevalonate pathway has been extensively studied for its involvement in cholesterol synthesis. Inhibition of this pathway using statins (3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors; HMGR inhibitors) is the primarily selected method due to its cholesterol-lowering effect, making statins the most commonly used (86-94%) cholesterol-lowering drugs in adults 1. This pathway has several other by-products that are affected by statins including GTPase molecules (guanine triphosphate-binding kinases), such as Rho/Rho-associated coiled kinase (ROCK) kinases, that are implicated in other diseases, including those of the central nervous system (CNS)...
January 12, 2016: Current Molecular Pharmacology
Leonardo Ermini, Martin Post, Isabella Caniggia
The mevalonate pathway synthesizes intermediates and products such as cholesterol and non-sterol isoprenoids that are crucial for cell survival and function. In the human placenta, the prenylation of proteins, rather than cholesterol synthesis, represents the main "metabolic target" of mevalonate metabolism. Major cellular functions depend on isoprenylation including proliferation, migration, metabolism and protein glycosylation that are all crucial for proper development of the embryo and the placenta. Statins are inhibitors of HMG-CoA reductase, the enzyme that catalyzes the reduction of HMG-CoA to mevalonic acid by NADPH...
January 12, 2016: Current Molecular Pharmacology
Kristin A Gabor, Michael B Fessler
It has become increasingly recognized that cholesterol and lipoproteins play significant roles in both lung physiology and the innate immune response. It is now known that the innate immune response and the cholesterol biosynthesis/trafficking network regulate one another, with important implications for pathogen invasion and host defense. The activation of pathogen recognition receptors and downstream cellular host defense functions are critically sensitive to cellular cholesterol. Conversely, microorganisms can co-opt the sterol/lipoprotein network in order to facilitate their own replication...
January 12, 2016: Current Molecular Pharmacology
Mohammad Hashemi, Reyhane Hoshyar, Sudharsana R Ande, Qi Min Chen, Claudia Solomon, Anne Zuse, Mohammad Naderi
The cholesterol biosynthesis pathway, also referred to as the mevalonate (MVA) pathway, is responsible for the biosynthesis of two key isoprenoids: farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Post-translational modification of small GTPases by FPP and GGPP has captured much attention due to their potential contribution to cancer, cardiovascular and neurodegenerative diseases. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) catalyzes the conversion of HMG-CoA to MVA, and is the rate-limiting step in the biosynthesis of cholesterol...
January 12, 2016: Current Molecular Pharmacology
Xiaodan Jiao, Niloufar Ashtari, Maryam Rahimi Balaei, Qi Min Chen, Ilnaz Badbezanchi, Shahla Shojaei, Adel Marzban, Nima Mirzaei, Seunghyuk Chung, Teng Guan, Jiasi Li, Jerry Vriend, Shahram Ejtemaei Mehr, Jiming Kong, Hassan Marzban
The mevalonate cascade is a key metabolic pathway that regulates a variety of cellular functions and is thereby implicated in the pathophysiology of most brain diseases, including neurodevelopmental and neurodegenerative disorders. Emerging lines of evidence suggest that statins and Rho GTPase inhibitors are efficacious and have advantageous properties in treatment of different pathologic conditions that are relevant to the central nervous system. Beyond the original role of statins in lowering cholesterol synthesis, they have anti-inflammatory, antioxidant and modulatory effects on signaling pathways...
January 12, 2016: Current Molecular Pharmacology
Pooneh Mokarram, Javad Alizadeh, Vahid Razban, Mahdi Barazeh, Claudia Solomon, Soudabeh Kavousipour
The metabolic steroid hormones, 17β stradiol (E2) and testosterone play roles in several functions including carbohydrate, lipid and protein metabolism, cellular signaling, cell proliferation, and cancer promotion. Steroid hormones have long been characterized as cell proliferation and differentiation regulators and are closely related to the development of breast and prostate cancers. In addition, cholesterol metabolism, mainly in adipose tissue, leads to the production of steroids and cytokines, thus increasing the risk of metabolic syndrome, obesity, and ER+ breast cancer in postmenopausal women...
January 12, 2016: Current Molecular Pharmacology
Alison L Müller, Darren H Freed
Inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by pharmaceuticals, commonly referred to as statins, has proven to be an effective and efficient way to reducing cholesterol levels in patients. As a result of this intervention, mevalonate production, formed during cholesterol synthesis, is inhibited. Mevalonate is the precursor to a variety of crucial downstream products, including those involved with the mitochondrial electron transport chain, and localized activation of small GTPases. Statins have also been observed to induce changes of the immune system, favouring a reduced pro-inflammatory phenotype...
January 12, 2016: Current Molecular Pharmacology
Neil C Thomson
Immunomodulatory effects of statins in vitro and in experimental models of asthma and COPD could potentially be relevant to the treatment of chronic airway diseases. This article provides an overview of the evidence from the key clinical studies on the effects of statins on clinical outcomes and inflammatory biomarkers in asthma and COPD. Future directions for clinical studies of statins in asthma and COPD are discussed. A small number of randomized controlled trials (RCTs) in adults with mild to moderate asthma suggest that short-term statin treatment does not improve lung function or symptom control, except for a possible improvement in quality of life and symptoms in smokers with asthma...
January 12, 2016: Current Molecular Pharmacology
Robert P Young, Raewyn J Hopkins
Current evidence suggests that persisting and/or exaggerated inflammation in the lungs initiated by smoking, and up-regulated through genetic susceptibility, may result in lung remodelling and impaired repair. The mevalonate pathway, through its modifying effects on innate immune responsiveness, may be involved in these processes providing a plausible pathogenic link between the development of chronic obstructive pulmonary disease (COPD) and lung cancer. The mevalonate pathway, mediates these effects through important intra-cellular signalling molecules called guanine phosphate transferases (GTPases) such as Rho-A...
January 12, 2016: Current Molecular Pharmacology
Ji Wu
No abstract text is available yet for this article.
2016: Current Molecular Pharmacology
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